Pigmentary retinopathy and nodular granuloma associated with acute retinal necrosis from varicella zoster virus and human herpes virus type 6: Case report

Rationale: Acute retinal necrosis (ARN) caused by human herpes virus type 6 (HHV-6) is uncommon. We described a case of consecutive bilateral ARN, which was found to be a coinfection of varicella zoster virus (VZV) and HHV-6 in a 50-year-old woman, not well responded with systemic acyclovir. We showed the atypical findings with corresponding fundus and optical coherence tomography imaging. Patient concerns: She presented with anterior segment inflammation with peripheral retinitis and vasculitis in the left eye with disease progression despite of initial antiviral treatment, end up with retinal detachment. The right eye, subsequently, developed focal retinitis. Diagnosis: ARN was diagnosed by clinical fundus picture, confirmed by polymerase chain reaction (PCR). Interventions: Initially, she was treated with intravenous acyclovir and intravitreal ganciclovir for left eye. Retinal necrosis progressed, followed by retinal detachment. Pars plana vitrectomy with silicone oil was performed. The right eye, subsequently, developed focal retinitis. Medication was switched to intravenous ganciclovir and then oral valganciclovir. Outcomes: Retinitis was resolved, generalized hyperpigmentation appeared as a salt-and-pepper appearance in the right eye. The left eye presented preretinal deposits on silicone-retina interphase along retinal vessels. Spectral-domain optical coherence tomography (SD-OCT) showed multiple hyperreflective nodules on retinal surface. Lessons: ARN from coinfection of VZV and HHV-6 is rare. Preretinal granulomas and generalized hyperpigmentation could be one of the HHV-6 features. HHV-6 should be in the differential diagnosis for ARN. It responds well to systemic ganciclovir.


Introduction
Acute retinal necrosis (ARN) is an infectious disease of the retina, first reported in 1971 by Urayama from Japan. [1] It presents full-thickness retinal necrosis at the peripheral retina together with prominent vitritis and occlusive vasculopathy. [2] The incidence of ARN was 0.63 cases per 1 million reported in the UK, [3] while 1.9% of patients with uveitis was diagnosed with ARN in a tertiary care hospital in Thailand. [4] Even though ARN is not a Consent for publication: Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. common disease, it can cause high morbidity and lead to blindness especially when the diagnosis and treatment are delayed. Varicella zoster virus (VZV) and herpes simplex virus (HSV) type1, 2 are the most common causes of the disease, however, some other viruses also constitute causative agents, such as Cytomegalovirus (CMV) and Epstein Barr virus (EBV). [2,5] We reported atypical clinical findings and refractory treatment response in ARN from coinfection of VZV and human herpes virus 6 (HHV-6).

Case report
In December 2020, a healthy 50-year-old Thai woman presented at Phramongkutklao Hospital with decreased vision and floaters in the left eye for 1 week. The patient had no underlying disease and relevant social and surgical history. Nevertheless, she reported a history of shingles around the neck 10 years ago.
Initial examination showed 20/100 visual acuity in the left eye using pinhole examination. Intraocular pressure was 11 mm Hg, and relative afferent pupillary defect was present in the left eye. The anterior segment revealed injected conjunctiva with corneal descemet fold, 3 + anterior chamber cells and multiple whitish mutton fat granulomatous keratic precipitates at Art triangle. Grade 1 vitreous haze with 2 + cells in the anterior vitreous, hyperemic optic disc with blurred margin, diffuse multiple whitish retinitis accompanied with arteriolitis and phlebitis at the peripheral retina were presented (Fig. 1A). The right eye was unremarkable with a visual acuity of 20/25 using pinhole examination. The patient received a diagnosis of ARN in the left eye and was admitted starting treatment with intravenous acyclovir 10 mg/kg/dose every 8 hours and supplemented with intravitreal 2 mg/0.1 mL ganciclovir injection in the left eye. The diagnosis was confirmed using aqueous polymerase chain reaction (PCR) in which VZV and HHV type 6 were detected. After starting treatment with acyclovir for 2 days, the patient received oral prednisolone 1 mg/kg/day to control the inflammation. Initial infectious workups were negative including anti-HIV, treponema pallidum hemagglutination and venereal disease research laboratory test. Chest X-ray was normal.
The confluence of retinal infiltration was observed. Retinitis and vasculitis had progressed to midperiphery after administering acyclovir and steroid for 5 days (Fig. 1B). The acyclovir was increased to 12 mg/kg/dose every 8 hours and prednisolone was discontinued. The clinical condition did not improve even though acyclovir had been administered for 17 days. Progressively confluent area of full-thickness retinal necrosis with inferior rhegmatogenous retinal detachment finally occurred (Fig. 2). The acyclovir increased to 15 mg/kg/dose and pars plana vitrectomy with silicone oil was performed. Vitreous samples were sent for bacterial and fungal    culture, cytology and PCR to determine the Herpesviridae family. VZV and HHV type 6 were detected, which were consistent with prior aqueous PCR results. Other work-up results were negative. After 3 weeks of intravenous acyclovir together with pars plana vitrectomy with silicone oil in the left eye, the retinitis did not subside. Furthermore, new retinitis foci developed at the inferonasal area of the far-peripheral retina in the right eye. We decided to switch the antiviral medication from intravenous acyclovir to ganciclovir 5 mg/kg/dose every 12 hours for 2 weeks followed by valganciclovir 450mg twice daily as a maintenance therapy for 4 months.
Three weeks after intravenous ganciclovir injection, retinitis was resolved in the right eye and turned to generalized hyperpigmentation, salt-and-pepper appearance, throughout the retina (Figs. 3A and 4A). Autofluorescence imaging showed hyper-and hypo-autofluorescence corresponding to color fundus photography (Fig. 4B). Spectral-domain optical coherence tomography (SD-OCT) at the points of hyperpigmentation lesions revealed thickening hyperreflective foci of retinal pigment epithelium ( Fig. 4C and D). Multiple roundshaped whitish granulomas deposited along both retinal arteries and veins and on the retinal surface around the posterior pole were detected in the left eye (Figs. 3B and 5A). SD-OCT showed multiple hyperreflective nodules on the retinal surface near the blood vessels showing as vertical hyperreflective oval lesions in the nerve fiber layer with shadowing (Fig. 5C). After continuing oral valganciclovir for 4 months, the granulomas along the vessels decreased in size but whitish preretinal granulomas appeared on the macular area in the left eye. However, the best corrected visual acuity, 20/20 in the right eye and finger count of 3 feet in the left eye, were unchanged. We decided to stop oral valganciclovir and closely follow up. After discontinuing oral valganciclovir for 2 months, the granulomas in the posterior pole decreased in size and number with time.

Discussion
We presented a case diagnosed with ARN with complete diagnostic criteria from the American Uveitis Society [6] including one or more foci of retinal necrosis with discrete borders, located in the peripheral retina, rapid progression in the absence of antiviral therapy, circumferential spreading, occlusive vasculopathy with arterial involvement, a prominent inflammatory reaction in the vitreous and anterior chamber and optic neuropathy. The aqueous and vitreous PCR confirmed positive for VZV and HHV-6 which were undetected in normal populations. [7] Many studies reported the Herpesviridae family such as VZV, HSV-1, HSV-2, CMV, and EBV [8][9][10][11] constituted a causative agent in ARN; however, little literature reported HHV-6 infection. [12][13][14][15][16] HHV-6 was the causative agent of exanthem subitum which was separated in 2 distinct viruses as HHV-6A and HHV-6B. HHV-6B was detected in intraocular inflammation more than HHV-6A which was usually detected in the central nervous system. [13] Our case clinically presented as ARN with a coinfection of VZV and HHV-6, without subtype differentiation due to laboratory limitations and was detected by PCR as the causative agent.
For optic neuritis and retinal vasculitis from HHV-6, in which inflammation is predominately caused by an immune response, systemic steroid alone was effective for treatment. [14] Nevertheless, in case of ARN, antiviral therapy was the mainstay of therapy. The patient responded well to acyclovir [15] while ganciclovir, foscarnet, cidofovir and long term valganciclovir were effective treatments in many case reports. [16][17][18][19] Hill JA [20] reported that high dose foscarnet 90 mg/kg every 12 hours and ganciclovir 5 mg/kg every 12 hours for induction were both similarly effective to treat HHV-6 base on clinical, [21] in vitro activity [22] and evidence of in vivo effectiveness. [23] As aforementioned, they might be the reason intravenous acyclovir combined with intravitreal ganciclovir and systemic steroid was ineffective at the beginning of the treatment in our patient. After switching intravenous acyclovir to intravenous ganciclovir, the clinical picture improved. However, long term valganciclovir was needed. In summary, our case received intravenous acyclovir for 3 weeks, then switched to intravenous ganciclovir for 2 weeks followed by oral valganciclovir for 4 months.
While receiving intravenous ganciclovir, the right fundus developed generalized hyperpigmentation which had never been reported in viral retinitis from VZV, HSV, EBV, or CMV. Generalized hyperpigmentation in our case appeared like the salt-and-pepper fundus picture of rubella infection which is also a viral infection. Even though unilateral pigmentary retinopathy is rare, it has been reported in acquired rubella infection among adult. [24] We postulated these clinical features were due to HHV-6. After rhegmatogenous retinal detachment was treated by vitrectomy with silicone oil in the left eye, the multiple preretinal nodular deposits on retinal surface along the arteries and veins in posterior pole were noted. The homogeneous hyperreflective deposits on the retinal surface nearby the blood vessels were seen in SD-OCT. These were similar to amorphous deposits [25] and preretinal granulomas [26][27][28][29] from toxoplasma retinochoroiditis. These nodules differed clinically from kyrieleis arteritis but had the same fluorescein angiography characteristics. [26] However, no further investigation was conducted to confirm toxoplasma infection in our case. On another thought, the nodular deposits could be the inflammatory reaction to silicone oil itself which has been reported as preretinal hyperreflective organized coarse material in silicone-retina interphase. [30] It had been observed in 14% of the patient undergoing retinal detachment surgery with silicone oil, similar to our scenario and disappeared after silicone oil removal. [30] In our case, it seemed to move posteriorly on the retinal surface from the perimacular area, initially along the vascular arcade, to the macular area. The nature of deposits appeared like movable nodules in the silicone-retina interphase which were stuck on the step of the prominent retinal vasculature and gravitational move to the macula. Finally, gradual resolution of the lesions was observed.

Conclusion
ARN from coinfection of VZV and HHV-6 is rare and difficult to treat. The preretinal granulomas and generalized hyperpigmentation after retinitis was resolved must be in the differential diagnosis of ARN from HHV-6. Intraocular fluid PCR is very useful for diagnosis. Furthermore, it responds well to intravenous ganciclovir treatment followed by oral valganciclovir.